Lactoferrin Enhances Growth and Reduces Nosocomial Infection in Preterm Infants

描述(申请人提供)：该项目旨在开发转铁蛋白(TLF，重组人乳铁蛋白)作为治疗早产儿的药物。该治疗将在出生后不久口服，以防止由于新生儿肠道上皮异常细菌入侵而引起的医院感染(NIS)，从而限制全身菌血症和坏死性小肠结肠炎(NEC)。据报道，住院新生儿中前瞻性研究的NIS总发病率为10.8 NI/100患者。发病率随出生体重降低而增加，极低出生体重组(出生体重1500g)高达81.8NI/100。来自国家儿童健康和人类发展研究所赞助的“新生儿网络”的最新数据表明，在NICU住院期间，29%的妊娠25至28周出生的婴儿和46%的怀孕不到25周的婴儿经历了严重的新生儿感染。医院感染最常见的部位是败血症和NEC。因此，我们将TLF的开发重点放在提供一种持续的方法来预防和治疗NIS对早产儿和出生时体重在750至1500克之间的婴儿的后果。这项研究将招募396名婴儿参加一项双盲、随机的前瞻性研究，除了标准的护理外，还将对24小时前的早产儿使用TLF或安慰剂。研究包括四个研究组：1)母乳+安慰剂，2)母乳+TLF，3)配方奶+安慰剂，4)配方奶+TLF。研究的第一阶段应确定口服TLF(剂量为300 mg/kg)30天时的安全性。采用(4×30)=120例患者，通过确定不良临床事件的发生率和严重程度，包括实验室和放射学异常，来评估TLF的安全性。预计不良事件可能与TLF无关，而是与早产有关，TLF可能会减轻早产的那些并发症[例如，支气管肺发育不良]。随后的连续第二阶段研究将确定TLF在促进出生后生长和减少医院感染(包括菌血症、肺炎、泌尿系感染、坏死性小肠结肠炎[NEC]加上“NEC恐慌”和脑膜炎)发生率方面的有效性。所有纳入研究的396名患者(第一阶段和第二阶段)将用于评估TLF的疗效。主要终点是恢复出生体重的时间、每日体重增加和出院天数、医院感染的发生率[迟发性菌血症、肺炎、坏死性小肠结肠炎、尿路感染和脑膜炎]以及无感染证据的“NEC恐慌”、“新生儿败血症综合征”或“全身炎症反应综合征”的发生率。此外，次级疗效参数应评估接受机械通气和/或鼻腔正压治疗的天数、补充氧气的天数以及总的发病率和死亡率(%)。已经成立了一个临床中心联盟，以确保有足够的病人数量和招聘率，以在项目启动后2年内完成该项目。该财团包括南伊利诺伊大学医学院(圣约翰儿童医院)、路易斯维尔大学(科萨尔儿童医院和路易斯维尔大学医院)和南加州大学(洛杉矶儿童医院和好莱坞长老会医学中心)。TLF在控制新生儿NIS方面的有效性可能会被合理地推广到其他患者群体。在美国，每年有200多万人(婴儿和成人)患上新城疫。这是一个重大的未得到满足的医疗需求，也是一个重要的市场。批准TLF用于治疗NIS对患者和社区都有很大的好处，也会有很大的商业价值。

DESCRIPTION (provided by applicant): This project aims to develop talactoferrin (TLF, recombinant human lactoferrin) as a therapeutic agent to treat prematurely born neonates. The treatment will be given orally shortly after birth to prevent nosocomial infections (NIs) due to abnormal bacterial invasion of neonatal intestinal epithelia and consequently to limit systemic bacteremia and necrotizing enterocolitis (NEC). The overall incidence of prospectively studied NIs in hospitalized neonates has been reported to be 10.8 NI/100 patients. The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight < 1500 g). Recent data from the National Institute of Child Health and Human Development-sponsored "Neonatal Network" indicated that 29% of infants born at 25 to 28 weeks' gestation and 46% of infants born at less than 25 weeks' gestation experience a serious NIs during hospitalization in the NICU. The most common NI sites were sepsis and NEC. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. The study shall enroll a total of 396 infants in a double-blind, randomized prospective study where TLF or placebo will be administered, in addition to the standard of care, to preterm infants before 24 hours of age. The study shall consist of four study groups: 1) mother's milk + placebo, 2) mother's milk + TLF, 3) formula feeding + placebo, and 4) formula feeding + TLF. The Phase-I part of the study shall determine the safety of TLF (at a dose of 300 mg/kg) when administered orally for 30 days. Using the total of (4 x 30) = 120 patients, safety of TLF shall be evaluated by determining the incidence and severity of adverse clinical events including laboratory and radiographic abnormalities. It is anticipated that adverse events might not be related to TLF, but rather to preterm birth, and TLF may mitigate those complications of prematurity [e.g., bronchopulmonary dysplasia]. The subsequent, continuous Phase-II part of the study shall ascertain the efficacy of TLF to enhance post-natal growth and to attenuate the incidence of nosocomial infections (including bacteremia, pneumonia, urinary infection, necrotizing enterocolitis [NEC] plus "NEC scares", and meningitis). All 396 patients recruited into the study (Phase I and Phase II) shall be used to evaluate efficacy of TLF. The Primary Endpoint shall be the time to regain birth weight, daily weight gain, and number of days to hospital discharge, Incidence of nosocomial infections [late-onset bacteremia, pneumonia, necrotizing enterocolitis, urinary tract infection, and meningitis] and incidence of "NEC Scares", "neonatal sepsis syndrome" or "systemic inflammatory response syndrome" without proven evidence of infection. Additionally, Secondary Efficacy Parameters shall evaluate the number of days on mechanical ventilation and/or nasal positive airway pressure, number of days on supplemental oxygen, and overall morbidity and mortality (%). A consortium of clinical centers has been formed to ensure adequate number of patients and the rate of recruitment to complete the project within 2 years from its initiation. The consortium includes the Southern Illinois University School of Medicine (St. John's Children's Hospital), The University of Louisville (Kosair Children's Hospital and the University of Louisville Hospital) and University of Southern California (Children's Hospital of Los Angeles and Hollywood Presbyterian Medical Center). Effectiveness of TLF in controlling NIs in neonates would likely find a logical extension to other populations of patients. More than 2,000,000 NIs occur each year in the USA (in infants and adults). This represents a major unmet medical need as well as a significant market. Marketing approval for TLF to treat NIs would be of great benefit to the patients and the community, and would also be of a substantial commercial value.